A process for the preparation of crisaborole

ABSTRACT

The present invention relates to a process for the preparation of crisaborole of formula (I): 
     
       
         
         
             
             
         
       
     
     by preparing intermediates of formulas (II) and (III):

The present invention relates to a process for the preparation ofCrisaborole, a non-steroidal medicament used for the treatment of atopicdermatitis. The invention also relates to novel synthesis intermediates.

TECHNICAL CONTEXT

Crisaborole is the international non-proprietary name of the compound5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole havingformula (I):

Crisaborole is the active ingredient of Eucrisa, a topical non-steroidalmedicament approved by the FDA in the USA for the treatment of atopicdermatitis in patients from two years old. The molecule is currentlyundergoing clinical trials (phase II) for the treatment of (inter alia)psoriasis.

Crisaborole and its synthesis route were described and claimed for thefirst time in patent application WO2006/089067 by Anacor PharmaceuticalInc. No alternative synthesis routes to the one described in theoriginator's patent and publications exist to date.

The synthesis route used in WO2006/089067 (scheme) involves numeroussteps, and the total yield is not very high, which makes the processexpensive.

US 2015/291629 discloses other boron-containing small molecules asanti-inflammatory agents.

It has surprisingly been found that by using a dichloroaryl intermediateof formula (V), as defined below, activated in the ortho position to thenitrile group by two electron-attracting groups, in particular twohalogens, the reactions indicated in the 2-bromo-hydroxybenzaldehydeprotection step (step 1) and the nucleophilic substitution reactionbetween the protected aldehyde and the fluorinated intermediate andsubsequent reduction of the resulting product (step 2) can be replacedby a one-pot reaction, thus eliminating several steps.

The process according to the invention produces Crisaborole with a highdegree of purity and excellent yields, and can be effected on anindustrial scale.

DESCRIPTION OF THE INVENTION

The object of the present invention is a process for the preparation ofCrisaborole of formula (I):

wherein said process comprises the following steps:

a) converting compound of formula (II):

to compound of formula (III):

in the presence of a tri (C₁-C₄) alkyl borate and a (C₄-C₆) alkyllithium or aryl lithium, and subsequent acidification of the reactionmedium; and

b) converting the resulting compound of formula (III) to Crisaborole offormula (I) by catalytic hydrogenation.

The process of the invention can comprise a further step for thepurification of Crisaborole, preferably by precipitating anacetone-water solution of the product in water.

The term (C₄-C₆) alkyl, as used herein, means a straight or branchedalkyl chain having 4 to 6 carbon atoms such as n-hexyl, n-pentyl,n-butyl, isobutyl, isopentyl or tert-butyl.

The term (C₁-C₄) alkyl, as used herein, means a straight or branchedalkyl chain having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl,isopropyl, n-butyl or isobutyl.

The (C₄-C₆) alkyl lithium used in step a) of the process described aboveis preferably selected from butyl lithium and hexyl lithium.

The tri (C₁-C₄) alkyl borate used in step a) is preferably selected fromtrimethyl borate and triisopropyl borate.

Step a) is effected in a polar aprotic solvent such as cyclic or linearethers or mixtures thereof, preferably tetrahydrofuran or methyltetrahydrofuran, at a temperature ranging between −30° and −80° C.

The reaction medium is preferably acidified with acids such ashydrochloric acid, sulphuric acid, acetic acid and formic acid, inparticular hydrochloric acid or acetic acid.

The catalytic hydrogenation of step b) is effected with palladium orplatinum catalysts supported on carbon, barium sulphate or bariumcarbonate, such as 5% palladium on carbon, in a solvent such as ether,alcohol or water or in mixtures, at a temperature ranging between 0° and50° C.

A further object of the invention is the process for the preparation ofCrisaborole of formula (I) as described above, wherein compound offormula (II) is obtained by the following steps:

-   -   i) reacting compound of formula (IV):

wherein X is —COH or —CH₂OH, with compound of formula (V):

-   -   in the presence of an inorganic base, to give compound of        formula (II) when X is —CH₂OH or compound of formula (VI) when X        is —COH:

-   -   and    -   ii) reducing compound of formula (VI) to give compound of        formula (II).

The nucleophilic substitution reaction of step i) is effected in polaraprotic solvents such as toluene, dimethyl formamide, dimethylacetamideand methyl isobutyl ketone or mixtures thereof, preferably dimethylformamide or dimethylacetamide, in the presence of inorganic bases suchas alkali metal or alkaline-earth metal carbonates, in particularpotassium carbonate.

The reaction is effected at a temperature ranging between 0° and 80° C.

The reduction reaction of step ii) is effected with reducing compoundssuch as KBH₄, NaBH₄ and LiBH₄ (potassium borohydride, sodium borohydrideand lithium borohydride), preferably NaBH₄, in polar aprotic solventssuch as THF, MeTHF, DMF and DMA (tetrahydrofuran, methyltetrahydrofuran,dimethylformamide, dimethylacetamide) or mixtures thereof, preferablytetrahydrofuran or methyltetrahydrofuran, at a temperature rangingbetween 0° and 50° C.

Another object of the invention is the process described above whereincompound of formula (IV), wherein X is —COH, is reacted with compound offormula (V), and steps i) and ii) are effected without isolatingcompound of formula (VI) (one-pot reaction).

Nucleophilic substitution reaction i) and reduction reaction ii),effected without isolating intermediate (VI), can be carried out byoperating in solvents such as DMF, DMA and toluene or mixtures thereof,where necessary adding a phase-transfer catalyst such astetrabutylammonium bromide, benzyl triethylammonium chloride, hexadecyltrimethylammonium bromide, tetrabutylammonium hydrogen sulphate andtetramethylammonium chloride (preferably tetrabutylammonium bromide).

Both reactions are effected at a temperature ranging between 0° and 120°C.

Compound of formula (IV) wherein X is —CH₂OH can be obtained by reducingcompound of formula (IV) wherein X is —COH. Compound of formula (IV)wherein X is —COH is a commercial product.

The reduction of compound of formula (IV) wherein X is —COH can beeffected in the presence of a reducing reagent such as potassiumborohydride, sodium borohydride or lithium borohydride, preferablysodium borohydride, in polar aprotic solvents selected fromtetrahydrofuran, dioxane, methyltetrahydrofuran, dimethyl formamide,dimethyl acetamide and toluene or mixtures thereof, preferablytetrahydrofuran or methyltetrahydrofuran.

The reaction is effected at a temperature ranging between 0 and 30° C.

Compound of formula V is a commercial product or obtainable by knownprocesses from commercial products.

A further object of the invention is the reaction intermediates offormulae (II) and (III).

Still a further object of the invention is a process for thepurification of Crisaborole, which comprises dropwise addition of anacetone:water mixture (5:1 to 8:1, preferably 7:1 w/w) of the compoundto water, followed by stirring at room temperature and filtration of theresulting precipitate.

Such process is advantageous as it allows excellent removal ofimpurities from the final product, particularly those deriving from thehydrogenation step of the process of the invention. The productresulting from said purification step has an X-ray diffraction spectrum(at Cuα wavelength) as reported in the FIG.

The process for the preparation of Crisaborole disclosed inWO2006/089067, and in Bioorg. Med. Chem. Lett: 19 (2009) 2129-2132 bythe same authors, involves five chemical steps and a total yield of 32%(mean values of the methods described), and involves lengthy reactions,with hot treatments (100° C.). The processing of the intermediatesinvolves distillations to dryness of large amounts of solvent, which areexpensive and not very safe. No less than four chemical steps (aldehydeprotection and alkylation, followed by deprotection and reduction) arerequired to obtain the key intermediate, and although they producefairly good yields, they are lengthy and expensive.

In a preferred embodiment thereof, the process of the invention,starting from 2-bromo-5-hydroxybenzaldehyde or the corresponding alcohol(2-bromo-5-hydroxy phenylmethanol), enables the key intermediate(4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile) to beprepared without isolating intermediates, operating at room temperature.The product is isolated by simple filtration after adding water asantisolvent to the reaction mixture. This is possible due to theaddition of two chlorine atoms to 4-fluoro benzonitrile, which activatethe aromatic nucleophilic substitution reaction. The two chlorine atomsare then removed to obtain Crisaborole by reduction. Despite theaddition of this step, the process of the invention only consists ofthree steps, as against five. The total yield is higher (74% vs. 32%),the operating conditions are milder, and the processes are simpler andsafer.

EXAMPLES Example 1 Synthesis of 4-bromo-3-(hydroxymethyl)phenol(Compound of Formula (IV) Wherein X is —CH₂OH)

2-Bromo-5-hydroxy benzaldehyde (compound of formula IV wherein X is—COH) (20.1 g, 100 mmol) was dissolved in THF (80 mL), and the solutionwas cooled to 0-5° C. A solution of NaBH₄ (1.9 g, 50 mmol) in water (10mL, stabilized with NaOH) was added in 30 min. The solution was stirredfor a further 30 min. Acetone (25 mL) was added dropwise to the solutionin 30 min. Water (50 mL) was then added, and THF was distilled off. Theresidual oil was extracted with AcOEt (200 mL). The organic phase waswashed with saline solution (50 mL), then AcOEt was distilled off. Theresulting solid was treated at 50° C. with 50 mL of toluene, and thesuspension cooled to 20° C. The solid was filtered and dried at 65° C.to obtain the title compound as a white solid (18.6 g, 91%).

¹H-NMR; 300 MHz, DMSO-d₆. δ 9.64 (brs, 1H), 7.27 (d, 1H), 7.01 (d, 1H),6.60 (dd, 1H), 5.37 (brs, 1H), 4.41 (s, 2H)

¹³C-NMR; 300 MHz, DMSO-d₆. δ 157.5, 142.4, 132.9, 115.9, 115.6, 109.4,63.0.

Example 2 Synthesis of4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of Formula(II)

4-Bromo-3-(hydroxymethyl)phenol (5.0 g, 25 mmols) (compound of formula(IV) wherein X is —CH₂OH) was dissolved in DMF (30 mL). 2,6 Dichloro-4fluorobenzonitrile (4.9 g, 26 mmol) (compound of formula (V)) and K₂CO₃(3.9 g, 28 mmols) were added, and the suspension was stirred for 5hours. Water (100 mL) was added, and compound of formula (II) wascollected as a white solid by filtration (7.3 g, 19.6 mmols, 80%).

¹H-NMR; 300 MHz, DMSO-d₆. δ 7.65 (d, 1H), 7.30 (d, 1H), 7.06 (dd, 1H),5.55 (t, 1H), 4.49, (d, 2H).

¹³C-NMR; 300 MHz, DMSO-d₆. δ 161.8, 153.6, 144.4, 139.1, 134.4, 120.9,102.1, 118.0, 117.4, 114.0, 107.5, 62.8.

Example 3 Synthesis of2,6-dichloro-4((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrileof Formula (III)

4-(4-Bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of formula(II) (50.0 g, 164 mmols), 3,4-dihydropyran (34.9 g, 415 mmols) andpyridinium p-toluenesulphonate (2.0 g, 8 mmols) were stirred in THF for24 hours. TiPrOB (49.2, 262 mmols) was added, and the solution wascooled to −78° C. A hexyllithium 2.3 molar solution in hexane was addeddropwise in 40 min., and the final mixture was stirred at saidtemperature for 90 min. The solution was heated to room temperature andkept under stirring at said temperature for a total of 2 hours. THF wasthen distilled off. 100 mL of 6N HCl was added slowly, and thesuspension was stirred for 16 hours. EtOH (400 mL) was added, andcompound of formula (III) was obtained by filtration (36.0 g, 112 mmols,84%).

¹H-NMR; 300 MHz, DMSO-d₆. δ 9.25 (s, 1H), 7.82 (d, 1H), 7.33 (s, 2H),7.23 (d, 1H), 7.15 (dd, 1H), 4.98 (s, 2H)

¹³C-NMR; 300 MHz, DMSO-d₆. δ 161.8, 157.2, 156.4, 139.1, 133.2, 119.6,118.4, 114.1, 113.7, 107.5, 70.1

Example 4 Synthesis of Crisaborole of Formula (I)

2,6-Dichloro-4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-benzonitrile(10.0 g, 31 mmols) and KOH (5.0 g, 84 mmols) were suspended in a mixtureof ethanol (100 mL) and water (100 mL). 5% Pd on carbon (1.0 g) was thenadded, and the mixture was placed under hydrogen atmosphere at 1-5 ATM.The reaction was completed after 1 h, and the catalyst was filtered off37% Hydrochloric acid was added to the filtered solution to obtain a pHof less than 2. The solution was concentrated under vacuum at 50 mL, anda white solid precipitated. The suspension was cooled to roomtemperature and stirred for 1 hour. Crisaborole was then isolated byfiltration (7.0 g, 28 mmol, 90%).

Example 5 Synthesis of4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile (One-PotReaction in DMA) of Formula (II)

2-Bromo-5-hydroxybenzaldehyde (30.0 g, 149 mmols) and2,6-dichloro-4-fluorobenzonitrile (30.0 g, 158 mmols) were dissolved inDMA (130 mL), and K₂CO₃ (27.0 g, 195 mmols) was added to the solution.The reaction was maintained at 20-30° C. for 3-6 hours, after which asolution of NaBH₄ (2.0 g, 53 mmols) in water (20 mL, stabilized with 5%NaOH) was added in 20 min. The solution was kept under stirring for afurther 30 min., then water (500 mL) was added. The solution was keptunder stirring for 1 hour, and the title product was isolated as a whitesolid by filtration (54.6 g, 146 mmols, 98%).

Example 6 Synthesis of4-(4-bromo-3-(formylphenoxy)-2,6-dichlorobenzonitrile of Formula (VI)

2-Bromo-5-hydroxy benzaldehyde (30.0 g, 149 mmols) was dissolved in DMF(120 mL), 2,6-dichloro-4-fluorobenzonitrile (30.0 g, 158 mmols) andK₂CO₃ (27.0 g, 195 mmols) were added to the solution, and the suspensionwas stirred for 1-4 h, maintaining the temperature under 30° C. Water(300 mL) was added, and a white solid was collected by filtration andwashing with water (100 mL). (54.2 g, 146 mmol, 97%).

¹H-NMR; 300 MHz, CDCl₃. δ 10.33 (s, 1H), 7.76 (d, 1H), 7.60 (d, 1H),7.22 (dd, 1H), 6.98 (s, 2H)

¹³C-NMR; 300 MHz, CDCl₃. δ 190.5, 160.6, 153.7, 139.9, 136.1, 135.2,127.3, 123.2, 117.3, 113.2, 109.1.

Example 7 Synthesis of4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of Formula(II)

4-(4-Bromo-3-formylphenoxy)-2,6-dichlorobenzonitrile (77.8 g, 210 mmols)was dissolved in THF (365 mL), and the solution was cooled to 0-5° C. Asolution of NaBH₄ (2.7 g, 71 mmols) in water (25 mL, stabilized by NaOH)was added in 1 hour. The solution was kept under stirring for a further30 min. Acetone (25 mL) was added dropwise in 30 min., then water (150mL) was added. THF was distilled off, and a solid precipitate wasobtained. The suspension was cooled to room temperature, and the productwas isolated as a white solid by filtration (77.6 g, 208 mmols, 98%).The crude product was suspended in toluene (320 mL) and placed underreflux for 30 minutes. The solution was slowly cooled to roomtemperature, and the pure white solid was recovered by filtration (75.3g, 95%).

Example 8 Synthesis of4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of Formula(II) (Phase-Transfer Conditions)

4-(4-Bromo-3-formylphenoxy)-2,6-dichlorobenzonitrile (15.0 g, 40 mmols)and TBAB (0.15 g, 0.5 mmols) were suspended in toluene (140 mL), and thesolution was heated to 45-50° C. A solution of NaBH₄ (0.6 g, 16 mmol) inwater (6 mL, stabilized with NaOH) was added in 10 min. The solution waskept under stirring for a further 60 min. Acetic acid (3.6 g) was addeddropwise in 30 min., and the mixture was then kept under stirring for 30min. The suspension was heated to 80° C., and the aqueous phase wasseparated. 70 mL of toluene was distilled off, and the solution wascooled to room temperature. The product was isolated as a white solid byfiltration (13.0 g, 35 mmols, 88%).

Example 9 Synthesis of4-(4-bromo-3-(hydroxymethyl)phenoxy)-2,6-dichlorobenzonitrile of Formula(II) (Reaction in Phase-Transfer Conditions)

2-Bromo-5-hydroxy-benzaldehyde (10.0 g, 50 mmols), 2,6-dichloro-4-fluorobenzonitrile (9.9 g, 52 mmols), K₂CO₃ (8.9 g, 64 mmols) and TBAB (1 g,0.3 mmols) were suspended in toluene (100 mL), and the solution washeated to 70° C. for 24 hours. The solution was cooled to roomtemperature and washed twice with water (50 ml). A solution of NaBH₄(0.65 g, 170 mmols) in water (15 mL) was added dropwise, and thesolution was kept under stirring for a further 30 min. The solution waswashed twice with water (50 mL) and concentrated to 40 mL. The solutionwas then cooled to room temperature, and the product was isolated as awhite solid by filtration (16.6 g, 44 mmols, 88%).

Example 10 Purification of Crisaborole

A Crisaborole (100 g) solution in a mixture of 350 g of acetone and 50 gof water was added dropwise to 1 liter of water at 25° C. during 30′.The resulting mixture was stirred for approx. 1-2 hrs. at roomtemperature, then filtered. Drying at 40° C. under vacuum yielded 96 gof product with chromatographic assay higher than 99.8%, having theX-ray diffraction spectrum (CuαK), the DSC and the HPLC as reported inthe FIGS. 1, 2 and 3 respectively.

1-15. (canceled)
 16. A process for the purification of Crisaborole whichcomprises dropwise addition of a 5:1 to 8:1 acetone:water mixture of thecompound to water, followed by stirring at room temperature andfiltration of the resulting product.
 17. A process according to claim 1comprising the dropwise addition of a 7:1 acetone:water mixture.
 18. Aprocess according to claim 1 wherein crisaborole of formula (I)

is obtained by: a) converting compound of formula (II):

into compound of formula (III):

in the presence of a tri (C₁-C₄) alkyl borate and a (C₄-C₆)alkyl lithiumor aryl lithium and subsequent acidification of the reaction medium; andb) converting the resulting compound of formula (III) into Crisaboroleof formula (I) by catalytic hydrogenation.